AB1255 PEGLOTICASE + METHOTREXATE COTHERAPY IN UNCONTROLLED GOUT PATIENTS WITH PRIOR PEGLOTICASE MONOTHERAPY FAILURE: FINDINGS OF THE ADVANCE OPEN-LABEL TRIAL
Authors: O. Troum, J. Botson, K. Obermeyer, S. Verma, B. Lamoreaux
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Pegloticase is often the last treatment option for patients (pts) with uncontrolled/‌refractory gout but anti-drug antibodies (ADAs) cause loss of serum urate [SU] lowering response and infusion reactions (IRs).<sup>[1]</sup> MIRROR RCT showed higher response rate (71% vs 39% during month 6) and lower IR risk (4% vs 31%) with methotrexate (MTX) cotherapy, which attenuated ADAs in pegloticase-naïve pts.<sup>[2]</sup> Therefore, retreating pts who previously developed ADAs with pegloticase monotherapy is clinically relevant. The ADVANCE trial examined pegloticase+MTX cotherapy safety and efficacy in pts with prior monotherapy failure. <h3>Objectives</h3> To report interim efficacy and safety findings of the ADVANCE open-label trial. <h3>Methods</h3> Pts with uncontrolled gout (SU ≥6 mg/dL, ULT failure/intolerance, and ≥1 symptom [≥1 tophus, ≥2 flares in past yr, or chronic gouty arthritis) who did not maintain SU-lowering during prior pegloticase monotherapy were included. Key exclusion criteria were prior moderate/severe IR or anaphylaxis to pegloticase, MTX contraindication, current immunosuppressant use, G6PD deficiency, and eGFR&lt;30 mL/min/1.73 m<sup>2</sup>. After a 6 wk MTX Run-in (subQ MTX titrated to 25 mg/wk [15 mg/wk if eGFR &lt;45]), pts began pegloticase (8 mg biweekly) + MTX Treatment for 24 wks (option to extend to 48 wks). Pts took 1 mg/d folic acid, gout flare prophylaxis, and pre-infusion IR prophylaxis (included 125 mg IV methylprednisolone). The primary endpoint was proportion with SU-lowering response during Month 6 (SU &lt;6 mg/dL for ≥80% of Wks 20-24). Other key endpoints were response rate during Month 3 (SU &lt;6 mg/dL for ≥80% of Wks 10-14) and IR rate. Safety was evaluated via AEs and laboratory monitoring. <h3>Results</h3> 13 pts began the MTX Run-in; 11 met study criteria and entered pegloticase+MTX Treatment (intent-to-treat population; 91% male, mean [±SD] age: 58.6±11.3 yrs, BMI: 31.8±5.4 kg/m<sup>2</sup>, eGFR: 70.2±15.8 [all ≥45]). SU before pegloticase exposure (Day 1) was 8.5±3.2 mg/dL and gout burden was high (gout history: 25.2±8.4 yrs, 91% had tophi, 4.5±3.8 flares in prior 6 months). Prior pegloticase course range was 2-27 infusions, with last infusion 3.7±2.4 yrs prior (range: 0.7─9.2 yrs). One pt (9%) was a responder during Month 3 and during Month 6 (ongoing treatment through Wk 30 at analysis). 8 pts (73%) met SU-discontinuation criteria (first SU &gt;6 mg/dL: 20.8±18.3 days after infusion 1), and 2 (18%) had moderate IRs. 7/13 pts (54%) had ≥1 AE during Run-in (1 SAE); 8/11 (73%) had ≥1 AE during Treatment (0 SAE, all Rheum CTC<sup>[3]</sup> grade 1 or 2), most commonly gout flare (<b>Table 1</b>). <h3>Conclusion</h3> Treatment response rate with pegloticase+MTX following failed monotherapy was 9%, markedly lower than in pegloticase-naïve pts (71%).<sup>[2]</sup> IR rate was 18%, higher than in pegloticase-naïve pts (4%),<sup>[2]</sup> but all were moderate (no anaphylaxis). These findings demonstrate the challenge of overcoming established ADAs against pegloticase and emphasize the importance of initiating immunomodulation before pegloticase therapy. <h3>References</h3> [1]Lipsky PE et al. <i>Arthritis Res Ther</i> 2014;16:R60 [2]Botson JK et al. <i>Arthritis Rheumatol</i> 2022 [Epub ahead of print] [3]Woodworth T et al. <i>J Rheumatol</i> 2007;34:1401-14 <h3>Acknowledgements</h3> This study was funded by Horizon Therapeutics plc. Medical writing and editing support provided by Lissa Padnick-Silver PhD, employee of and stockholder in Horizon. <h3>Disclosure of Interests</h3> Orrin Troum Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Horizon, Novartis, Pfizer Inc, Sanofi-Genzyme, Takeda, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Horizon, Lilly, Pfizer, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Centocor, Corrona, Horizon, Novartis, Pfizer, John Botson Speakers bureau: Abbvie, Amgen, Aurinia, Chemocentryx, Horizon, Lilly, Novartis, Consultant of: Abbvie, Amgen, Aurinia, Chemocentryx, Horizon, Lilly, Novartis, Grant/research support from: Allena, Horizon, Radius Health, Katie Obermeyer Shareholder of: Horizon, Employee of: Horizon, Supra Verma Shareholder of: Horizon, Employee of: Horizon, Brian LaMoreaux Shareholder of: Horizon, Employee of: Horizon.